Antibacterial antiplaque oral composition

ABSTRACT

An oral composition dentifrice comprising an orally acceptable vehicle, about 5-30% by weight of a siliceous polishing agent, a substantially water-insoluble noncationic antibacterial antiplaque agent, such as 2,4,4&#39;-trichloro-2&#39;-hydroxydiphenyl ether (triclosan), and an antibacterial-enhancing agent which enhances the delivery of said antibacterial agent to, and retention thereof on, oral surfaces, wherein said antiplaque agent is substantially completely dissolved in saliva present during tooth and gum cleaning in a solubilizing agent therefor. The solubilizing agent may be a humectant polyol such as propylene glycol, dipropylene glycol and hexylene glycol; a cellosolve such as methyl cellosolve and ethyl cellosolve; a vegetable oil or wax containing at least about 12 carbon atoms in a straight chain such as olive oil, castor oil and petrolatum; or an ester such as ethyl acetate, amyl acetate, glyceryl tristearate and benzyl benzoate.

This is a division of application Ser. No. 07/754,887 filed Sep. 6, 1991now U.S. Pat. No. 5,192,530, granted Mar. 9, 1993 which is acontinuation of application Ser. No. 07/398,606 filed Aug. 25, 1989, nowabandoned, which is a continuation-in-part of application Ser. No.07/291,712 filed Dec. 29, 1988, now U.S. Pat. No. 4,894,220 granted Jan.16, 1990, and of application Ser. No. 07/346,258 filed May 1, 1989, nowU.S. Pat. No. 5,043,154 granted Aug. 27, 1991, which are respectively acontinuation-in-part and a continuation of application Ser. No.07/008,901, filed Jan. 30, 1987, now abandoned.

This invention relates to an antibacterial antiplaque oral compositiondentifrice. More particularly, it relates to an oral compositiondentifrice containing a substantially water-insoluble noncationicantibacterial agent effective to inhibit plaque.

Dental plaque is a soft deposit which forms on teeth as opposed tocalculus which is a hard calcified deposit on teeth. Unlike calculus,plaque may form on any part of the tooth surface, particularly includingat the gingival margin. Hence, besides being unsightly, it is implicatedin the occurence of gingivitis.

Accordingly, it is highly desirable to include antimicrobial agentswhich have been known to reduce plaque in oral compositions. Frequently,cationic antibacterial agents have been suggested. Moreover, in U.S.Pat. No. 4,022,880 to Vinson et al, a compound providing zinc ions as ananticalculus agent is admixed with an antibacterial agent effective toretard the growth of plaque bacteria. A wide variety of antibacterialagents are described with the zinc compounds including cationicmaterials such as guanides and quaternary ammonium compounds as well asnon-cationic compounds such as halogenated salicylanilides andhalogentated hydroxydiphenyl ethers. The noncationic antibacterialantiplaque halogentated hydroxydiphenyl ether, triclosan, has also beendescribed in combination with zinc citrate trihydrate in European PatentPublication 0161,899 to Saxton et al.

The cationic antibacterial materials such as chlorhexidine, benzthoniumchloride and cetyl pyridinium chloride have been the subject of greatestinvestigation as antibacterial antiplaque agents. However, they aregenerally not effective when used with anionic materials. Noncationicantibacterial materials, on the other hand, can be compatible withanionic components in an oral composition.

However, oral compositions typically are mixtures of numerous componentsand even such typically neutral materials as humectants can affectperformance of such compositions.

It is an advantage of this invention that an oral composition dentifricecontaining a substantially waterinsoluble noncationic antibacterialagent and an antibacterial-enhancing agent which enhances the deliveryof said antibacterial agent to, and retention thereof on, oral surfacesis provided to inhibit plaque formation.

It is an advantage of this invention that said antibacterial-enhancingagents enhance the delivery and retention of the antibacterial agent onteeth and on soft oral tissues.

It is a further advantage of this invention that such an oralcomposition is provided with a solubilizing agent which dissolves thenoncationic antibacterial agent for effective delivery onto soft oraltissues.

It is a further advantage of this invention that an antiplaque oralcomposition is provided which is effective to reduce the occurence ofgingivitis.

Additional advantages of this invention will be apparent fromconsideration of the following specification.

In accordance with certain of its aspects, this invention relates to anoral composition dentifrice comprising in an orally acceptable vehicle,about 5-30% by weight of a siliceous polishing agent, an effectiveantiplaque amount of a substantially water insoluble noncationicantibacterial agent, and about 0.05-4% by weight of anantibacterial-enhancing agent which enhances the delivery of saidantibacterial agent to, and retention thereof on, oral surfaces, whereinsaid oral composition comprises a solubilizing material for saidantibacterial agent in amount sufficient to dissolve said antibacterialagent in saliva. Typical examples of water insoluble noncationicantibacterial agents which are particularly desirable fromconsiderations of antiplaque effectiveness, safety and formulation are:

Halogenated Diphenyl Ethers

2',4,4'-trichloro-2-hydroxy-diphenyl ether (Triclosan)

2,2'-dihydroxy-5,5'-dibromo-diphenyl ether.

Halogenated Salicylanilides

4',5-dibromosalicylanilide

3,4',5-trichlorosalcylanilide

3,4',5-tribromosalicylanilide

2,3,3',5-tetrachlorosalicylanilide

3,3,3',5-tetrachlorosalicylanilide

3,5-dibromo-3'-trifluoromethyl salicylanilide

5-n-octanoyl-3'-trifluoromethyl salicylanilide

3,5-dibromo-4'-trifluoromethyl salicylanilide

3,5-dibromo-3'-trifluoro methyl salicylanilide (fluorophene)

    ______________________________________                                        Benzoic Esters                                                                ______________________________________                                        Methyl                                                                        p-Hydroxybenzoic Ester                                                        Ethyl                                                                         p-Hydroxybenzoic Ester                                                        Propyl                                                                        p-Hydroxybenzoic Ester                                                        Butyl                                                                         p-Hydroxybenzoic Ester                                                        ______________________________________                                    

Halogenated Carbanilides

3,4,4'-trichlorocarbanilide

3-trifluoromethyl-4,4'-dichlorocarbanilide

3,3,4'-trichlorocarbanilide

Phenolic Compounds (including phenol and its homologs, mono- andpoly-alkyl and aromatic halo (e.g. F, Cl, Br, I)--phenols, resorcinoland catechol and their derivatives and bisphenolic compounds). Suchphenolic compounds include inter alia:

    ______________________________________                                         Phenol and its Homologs                                                      ______________________________________                                               Phenol                                                                        2 Methyl                                                                      Phenol                                                                        3 Methyl                                                                      Phenol                                                                        4 Methyl                                                                      Phenol                                                                        4 Ethyl                                                                       Phenol                                                                        2,4-Dimethyl                                                                  Phenol                                                                        2,5-Dimethyl                                                                  Phenol                                                                        3,4-Dimethyl                                                                  Phenol                                                                        2,6-Dimethyl                                                                  Phenol                                                                        4-n Propyl                                                                    Phenol                                                                        4-n-Butyl                                                                     Phenol                                                                        4-n-Amyl                                                                      Phenol                                                                        4-tert-Amyl                                                                   Phenol                                                                        4-n-Hexyl                                                                     Phenol                                                                        4-n-Heptyl                                                                    Phenol                                                                 ______________________________________                                    

2-Methoxy-4-(2-Propenyl)-Phenol (Eugenol) 2-Isopropyl-5-Methyl-Phenol(Thymol)

    ______________________________________                                        Mono- and Poly-Alkyl and Aralkyl Halophenols                                  ______________________________________                                        Methyl                                                                        p-Chlorophenol                                                                Ethyl                                                                         p-Chlorophenol                                                                n-Propyl                                                                      p-Chlorophenol                                                                n-Butyl                                                                       p-Chlorophenol                                                                n-Amyl                                                                        p-Chlorophenol                                                                sec-Amyl                                                                      p-Chlorophenol                                                                n-Hexyl                                                                       p-Chlorophenol                                                                Cyclohexyl                                                                    p-Chlorophenol                                                                n-Heptyl                                                                      p-Chlorophenol                                                                n-Octyl                                                                       p-Chlorophenol                                                                O-Chlorophenol                                                                Methyl                                                                        o-Chlorophenol                                                                Ethyl                                                                         o-Chlorophenol                                                                n-Propyl                                                                      o-Chlorophenol                                                                n-Butyl                                                                       o-Chlorophenol                                                                n-Amyl                                                                        o-Chlorophenol                                                                tert-Amyl                                                                     o-Chlorophenol                                                                n-Hexyl                                                                       o-Chlorophenol                                                                n-Heptyl                                                                      o-Chlorophenol                                                                p-Chlorophenol                                                                o-Benzyl                                                                      p-Chlorophenol                                                                o-Benzyl-m-methyl                                                             p-Chlorophenol                                                                o-Benzyl-m, m-dimethyl                                                        p-Chlorophenol                                                                o-Phenylethyl                                                                 p-Chlorophenol                                                                o-Phenylethyl-m-methyl                                                        p-Chlorophenol                                                                3-Methyl                                                                      p-Chlorophenol                                                                3,5-Dimethyl                                                                  p-Chlorophenol                                                                6-Ethyl-3-methyl                                                              p-Chlorophenol                                                                6-n-Propyl-3-methyl                                                           p-Chlorophenol                                                                6-iso-propyl-3-methyl                                                         p-Chlorophenol                                                                2-Ethyl-3,5-dimethyl                                                          p-Chlorophenol                                                                6-sec Butyl-3-methyl                                                          p-Chlorophenol                                                                2-iso-Propyl-3,5-dimethyl                                                     p-Chlorophenol                                                                6-Diethylmethyl-3-methyl                                                      p-Chlorophenol                                                                6-iso-Propyl-2-ethyl-3-methyl                                                 p-Chlorophenol                                                                2-sec Amyl-3-5-dimethyl                                                       p-Chlorophenol                                                                2-Diethylmethyl-3,5-dimethyl                                                  p-Chlorophenol                                                                6-sec Octyl-3-methyl                                                          p-Chlorophenol                                                                p-Bromophenol                                                                 Methyl                                                                        p-Bromophenol                                                                 Ethyl                                                                         p-Bromophenol                                                                 n-Propyl                                                                      p-Bromophenol                                                                 n-Butyl                                                                       p-Bromophenol                                                                 n-Amyl                                                                        p-Bromophenol                                                                 sec-Amyl                                                                      p-Bromophenol                                                                 n-Hexyl                                                                       p-Bromophenol                                                                 cyclohexyl                                                                    p-Bromophenol                                                                 o-Bromophenol                                                                 tert-Amyl                                                                     o-Bromophenol                                                                 n-Hexyl                                                                       o-Bromophenol                                                                 n-Propyl-m,m-Dimethyl                                                         o-Bromophenol                                                                 2-Phenyl Phenol                                                               4-Chloro-2-methyl phenol                                                      4-chloro-3-methyl phenol                                                      4-chloro-3,5-dimethyl phenol                                                  2,4-dichloro-3,5-dimethyl phenol                                              3,4,5,6-tetrabromo-2-methylphenol                                             5-methyl-2-pentylphenol                                                       4-isopropyl-3-methylphenol                                                    5-chloro-2-hydroxydiphenyl methane                                            ______________________________________                                    

    ______________________________________                                         Resorcinol and Its Derivatives                                               ______________________________________                                        Resorcinol                                                                    Methyl                                                                        Resorcinol                                                                    Ethyl                                                                         Resorcinol                                                                    n-Propyl                                                                      Resorcinol                                                                    n-Butyl                                                                       Resorcinol                                                                    n-Amyl                                                                        Resorcinol                                                                    n-Hexyl                                                                       Resorcinol                                                                    n-Heptyl                                                                      Resorcinol                                                                    n-Octyl                                                                       Resorcinol                                                                    n-Nonyl                                                                       Resorcinol                                                                    Phenyl                                                                        Resorcinol                                                                    Benzyl                                                                        Resorcinol                                                                    Phenylethyl                                                                   Resorcinol                                                                    Phenylpropyl                                                                  Resorcinol                                                                    p-Chlorobenzyl                                                                Resorcinol                                                                    5-Chloro                                                                      2,4-Dihydroxydiphenyl Methane                                                 4'-Chloro                                                                     2,4-Dihydroxydiphenyl Methane                                                 5-Bromo                                                                       2,4-Dihydroxydiphenyl Methane                                                 4'-Bromo                                                                      2,4-Dihydroxydiphenyl Methane                                                 ______________________________________                                    

Bisphenolic Compounds

Bisphenol A

2,2'-methylene bis (4-chlorophenol)

2,2'-methylene bis (3,4,6-trichlorophenol) (hexachlorophene)

2,2'-methylene bis (4-chloro-6-bromophenol)

bis (2-hydroxy-3,5-dichlorophenyl) sulfide

bis (2-hydroxy-5-chlorobenzyl) sulfide

The noncationic antibacterial agent is present in the oral compositionin an effective antiplaque amount, typically about 0.01-5% by weight,preferably about 0.03-1% and most preferably about 0.3-0.5%. Theantibacterial agent is substantially water-insoluble, meaning that itssolubility is less than about 1% by weight in water at 25° C. and may beeven less than about 0.1%.

The preferred halogenated diphenyl ether is triclosan. The preferredphenolic compounds are phenol, thymol, eugenol, hexyl resorcinol and2,2'methylene bis (4-chloro-6-bromophenol). The most preferredantibacterial antiplaque compound is triclosan. Triclosan is disclosedin aforementioned U.S. Pat. No. 4,022,880 as an antibacterial agent incombination with an anticalculus agent which provides zinc ions and inGerman Patent Disclosure 3,532,860 in combination with a coppercompound. In European Patent Disclosure 0278744 it is disclosed incombination with a tooth desensitizing agent containing a source ofpotassium ions. It is also disclosed as an antiplaque agent in adentifrice formulated to contain a lamellar liquid crystal surfactantphase having a lamellar spacing of less than 6.0 nm and which mayoptionally contain a zinc salt in published European Patent Application0161898 of Lane et al and in a dentifrice containing zinc citratetrihydrate in published European Patent Application 0161899 to Saxton etal. In European Patent Application 271332 a typical drug release systemwhich could include triclosan in a toothpaste is described whichcontains a solubilizing agent such as propylene glycol.

The antibacterial-enhancing agent (AEA) which enhances delivery of saidantibacterial agent to, and retention thereof on, oral surfaces, isemployed in amounts effective to achieve such enhancement within therange in the oral composition of about 0.05% to about 4%, preferablyabout 0.1% to about 3%, more preferably about 0.5% to about 2.5% byweight.

AEA polymeric materials of the present invention include those which canbe characterized as having utility as dentifrice adhesives or fixativesor dental cements. For example, U.S. Pat. Nos. 4,521,551 and 4,375,036,each to Chang et al, describe commercially available copolymer ofmethylvinyl ether-maleic anhydride (Gantrez) as a denture fixative.However, there has not been recognition in the prior art that adhesives,fixatives or cements when applied in water soluble or water swellableform together with substantially water insoluble non-cationicantibacterial antiplaque agents could enhance the antibacterial activityof such agents. Further, in U.S. Pat. No. 4,485,090 to Chang, Gantrez ANcopolymer is mentioned among polymeric anionic membrane-formingmaterials which attach to a tooth surface to form a hydrophobic barrierwhich reduces elution of a previously applied therapeutic cariesprophylactic fluoride compound. Again, there is no recognition that suchpolymeric material could enhance the antibacterial activity ofsubstantially water insoluble non-cationic antibacterial antiplaqueagents.

This AEA may be a simple compound, preferably a polymerizable monomer,more preferably a polymer, which latter term is entirely generic,including for example oligomers, homopolymers, copolymers of two or moremonomers, ionomers, block copolymers, graft copolymers, cross-linkedpolymers and copolymers, and the like. The AEA may be natural orsynthetic, and water insoluble or preferably water (saliva) soluble orswellable (hydratable, hydrogel forming). It has an (weight) averagemolecular weight of about 100 to about 1,000,000, preferably about 1,000to about 1,000,000, more preferably about 2,000 or 2,500 to about250,000 or 500,000.

The AEA ordinarily contains at least one delivery-enhancing group, whichis preferably acidic such as sulfonic, phosphinic, or more preferablyphosphonic or carboxylic, or salt thereof, e.g. alkali metal orammonium, and at least one organic retention-enhancing group, preferablya plurality of both the delivery-enhancing and retention-enhancinggroups, which latter groups preferably have the formula --(X)_(n) --Rwherein X is O, N, S, SO, SO₂, P, PO or Si or the like, R is hydrophobicalkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic or theirinert-substituted derivatives, and n is zero or 1 or more. The aforesaid"inert-substituted derivatives", are intended to include substituents orR which are generally non-hydrophilic and do not significantly interferewith the desired functions of the AEA as enhancing the delivery of theantibacterial agent to, and retention thereof on, oral surfaces such ashalo, e.g. Cl, Br, I, and carbo and the like. Illustrations of suchretention-enhancing groups are tabulated below.

    ______________________________________                                        n   X        --(X).sub.n R                                                    ______________________________________                                        0   --       methyl, ethyl, propyl, butyl, isobutyl, t-butyl,                              cyclohexyl, allyl, benzyl, phenyl, chlorophenyl,                              xylyl, pyridyl, furanyl, acetyl, benzoyl, butyryl,                            terephthaloyl, etc.                                              1   O        ethoxy, benzyloxy, thioacetoxy, phenoxy,                                      carboethoxy, carbobenzyloxy, etc.                                    N        ethylamino, diethylamino, propylamido,                                        benzylamino, benzoylamido, phenylacetamido, etc.                     S        thiobutyl, thioisobutyl, thioallyl, thiobenzyl,                               thiophenyl, thiopropionyl, phenylthioacetyl,                                  thiobenzoyl, etc.                                                    SO       butylsulfoxy, allylsulfoxy, benzylsulfoxy,                                    phenylsulfoxy, etc.                                                  S.sub.2  butylsulfonyl, allysulfonyl, benzylsulfonyl,                                  phenylsulfonyl, etc.                                                 P        diethyphosphinyl, ethylvinylphosphinyl,                                       ethylallylphosphinyl, ethylbenzylphosphinyl,                                  ethylphenylphosphinyl, etc.                                          PO       diethylphosphinoxy, ethylvinylphosphinoxy,                                    methylallylphosphinoxy, methylbenzyphosphinoxy,                               methylphenylphosphinoxy, etc.                                        Si       trimethysilyl, dimethylbutylsilyl,                                            dimethylbenzylsilyl, dimethylvinylsilyl,                                      dimethylallylsilyl, etc.                                         ______________________________________                                    

As employed herein, the delivery-enhancing group refers to one whichattaches or substantively, adhesively, cohesively or otherwise bonds theAEA (carrying the antibacterial agent) to oral (e.g. tooth and gum)surfaces, thereby "delivering" the antibacterial agent to such surfaces.The organic retention-enhancing group, generally hydrophobic, attachesor otherwise bonds the antibacterial agent to the AEA, thereby promotingretention of the antibacterial agent to the AEA and indirectly on theoral surfaces. In some instances, attachment of the antibacterial agentoccurs through physical entrapment thereof by the AEA, especially whenthe AEA is a cross-linked polymer, the structure of which inherentlyprovides increased sites for such entrapment. The presence of a highermolecular weight, more hydrophobic cross-linking moiety in thecross-linked polymer still further promotes the physical entrapment ofthe antibacterial agent to or by the cross-linked AEA polymer.

Preferably, the AEA is an anionic polymer comprising a chain or backbonecontaining repeating units each preferably containing at least onecarbon atom and preferably at least one directly or indirectly pendant,monovalent delivery-enhancing group and at least one directly orindirectly pendant monovalent retention-enhancing group geminally,vicinally or less preferably otherwise bonded to atoms, preferablycarbon, in the chain. Less preferably, the polymer may containdelivery-enhancing groups and/or retention-enhancing groups and/or otherdivalent atoms or groups as links in the polymer chain instead of or inaddition to carbon atoms, or as cross-linking moieties.

It will be understood that any examples or illustrations of AEA'sdisclosed herein which do not contain both delivery-enhancing groups andretention enhancing groups may and preferably should be chemicallymodified in known manner to obtain the preferred AEA's containing bothsuch groups and preferably a plurality of each such groups. In the caseof the preferred polymeric AEA's, it is desirable, for maximizingsubstantivity and delivery of the antibacterial agent to oral surfaces,that the repeating units in the polymer chain or backbone containing theacidic delivery enhancing groups constitute at least about 10%,preferably at least about 50%, more preferably at least about 80% up to95% or 100% by weight of the polymer.

According to a preferred embodiment of this invention, the AEA comprisesa polymer containing repeating units in which one or more phosphonicacid delivery-enhancing groups are bonded to one or more carbon atoms inthe polymer chain. An example of such an AEA is poly (vinyl phosphonicacid) containing units of the formula: ##STR1## which however does notcontain a retention-enhancing group. A group of the latter type wouldhowever be present in poly (1-phosphonopropene) with units of theformula: ##STR2## A preferred phosphonic acid-containing AEA for useherein is poly (beta styrene phosphonic acid) containing units of theformula: ##STR3## wherein Ph is phenyl, the phosphonicdelivery-enhancing group and the phenyl retention-enhancing group beingbonded on vicinal carbon atoms in the chain, or a copolymer of betastyrene phosphonic acid with vinyl phosphonyl chloride having the unitsof the foregoing formula III alternating or in random association withunits of formula I above, or poly (alpha styrene phosphonic acid)containing units of the formula: ##STR4## in which the delivery-andretention-enhancing groups are geminally bonded to the chain.

These styrene phosphonic acid polymers and their copolymers with otherinert ethylenically unsaturated monomers generally have molecularweights in the range of about 2,000 to about 30,000, preferably about2,500 to about 10,000. Such "inert" monomers do not significantlyinterfere with the intended function of any copolymer employed as an AEAherein.

Other phosphonic-containing polymers include, for example, phosphonatedethylene having units of the formula.

    --[CH.sub.2).sub.14 CHPO.sub.3 H.sub.2 ].sub.n --

where n may for example be an integer or have a value giving the polymera molecular weight of about 3,000; and sodium poly(butene-4,4-diphosphonate) having units of the formula: ##STR5## andpoly (allyl bis (phosphonoethyl) amine) having units of the formula:##STR6## Other phosphonated polymers, for example poly (allyl phosphonoacetate), phosphonated polymethacrylate, etc. and the geminaldiphosphonate polymers disclosed in EP Publication 0321233 may beemployed herein as AEA's, provided of course that they contain or aremodified to contain the above-defined organic retention-enhancinggroups.

The alpha- and beta- styrene phosphonic acid polymers and copolymerswith other ethylenically unsaturated monomers may in general be preparedby heating the monomers or mixtures of monomers, preferably undernitrogen, in the presence of an effective amount, e.g. about 3-5%, of aradical initiator, e.g. AIBN, benzoyl peroxide, t-butyl hydroperoxide,persulfate or the like, neat or as solutions in an inert solution suchas acetonitrile, methylene chloride or 1,2-dichloromethane; at elevatedtemperatures, e.g. about 125° C. or at solvent reflux, for periods ofabout 8 to 200 hours. The crude polymeric products after removal of anyinert solvent, is mixed with water and the aqueous mixture adjusted to apH of about 8-10, e.g. with aqueous sodium hydroxide. After filtrationof any solid impurities, the filtrate solution is dialyzed against water(e.g. at 3500 Dalton cutoff), and the purified polymer isolated from theretentate solution as by lyophylization.

According to another preferred embodiment, the AEA may comprise asynthetic anionic polymeric polycarboxylate. Although not used in thepresent invention to coact with polyphosphate anticalculus agent,synthetic anionic polymeric polycarboxylate having a molecular weight ofabout 1,000 to about 1,000,000, preferably about 30,000 to about500,000, has been used as an inhibitor of alkaline phosphatase enzyme inoptimizing anticalculus effectiveness of linear molecularly dehydratedpolyphosphate salts, as disclosed in U.S. Pat. No. 4,627,977 to Gaffaret al. Indeed, in published British Patent Publication 22 00551, thepolymeric polycarboxylate is disclosed as an optional ingredient in oralcompositions containing linear molecularly dehydrated polyphosphatesalts and noncationic antibacterial agent. It is further observed, inthe context of the present invention that such polycarboxylate whencontaining or modified to contain retention-enhancing groups is markedlyeffective to enhance delivery and retention of the noncationicantibacterial, antiplaque agent to dental surfaces when anotheringredient with which the polymeric polycarboxylate would coact (thatis, molecularly dehydrated polyphosphate) is absent; for instance, whenthe ingredient with which the polymeric polycarboxylate coacts isespecially the noncationic antibacterial agent.

Synthetic anionic polymeric polycarboxylates and their complexes withvarious cationic germicides, zinc and magnesium have been previouslydisclosed as anticalculus agents per se in, for example U.S. Pat. No.3,429,963 to Shedlovsky; U.S. Pat. No. 4,152,420 to Gaffar; U.S. Pat.No. 3,956,480 to Dichter et al; U.S. Pat. No. 4,138,477 to Gaffar; andU.S. Pat. No. 4,183,914 to Gaffar et al. It is to be understood that thesynthetic anionic polymeric polycarboxylates so disclosed in theseseveral patents when containing or modified to contain theretention-enhancing groups defined above are operative as AEA's in thecompositions and methods of this invention and such disclosures are tothat extent incorporated herein by reference thereto.

These synthetic anionic polymeric polycarboxylates are often employed inthe form of their free acids or preferably partially or more preferablyfully neutralized water soluble or water-swellable (hydratable, gelforming) alkali metal (e.g. potassium and preferably sodium) or ammoniumsalts. Preferred are 1:4 to 4:1 copolymers of maleic anhydride or acidwith another polymerizable ethylenically unsaturated monomer, preferablymethyl vinyl ether/maleic anhydride having a molecular weight (M.W.) ofabout 30,000 to about 1,000,000, more preferably about 30,000 to about500,000. These copolymers are available for example as Gantrez e.g. AN139 (M.W. 500,000), A.N. 119 (M.W. 250,000); and preferably S-97Pharmaceutical Grade (M.W. 70,000), of GAF Corporation.

Other AEA-operative polymeric polycarboxylates containing or modified tocontain retention-enhancing groups include those disclosed in U.S. Pat.No. 3,956,480 referred to above, such as the 1:1 copolymers of maleicanhydride with ethyl acrylate, hydroxyethyl methacrylate,N-vinyl-2-pyrollidone, or ethylene, the latter being available forexample as Monsanto EMA No. 1103 M.W. 10,000 and EMA Grade 61, and 1:1copolymers of acrylic acid with methyl or hydroxyethyl methacrylate,methyl or ethyl acrylate, isobutyl, isobutyl vinyl ether orN-vinyl-2-pyrrolidone.

Additional operative polymeric polycarboxylates disclosed in abovereferred to U.S. Pat. Nos. 4,138,477 and 4,183,914, containing ormodified to contain retention enhancing groups include copolymers ofmaleic anhydride with styrene, isobutylene or ethyl vinyl ether,polyacrylic, polyitaconic and polymaleic acids, and sulfoacrylicoligomers of M.W. as low as 1,000, available as Uniroyal ND-2.

Suitable generally are retention-enhancing group-containing polymerizedolefinically or ethylenically unsaturated carboxylic acids containing anactivated carbon-to-carbon olefinic double bond and at least onecarboxyl group, that is, an acid containing an olefinic double bondwhich readily functions in polymerization because of its presence in themonomer molecule either in the alpha-beta position with respect to acarboxyl group or a part of a terminal methylene grouping. Illustrativeof such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic,crontonic, beta-acryloxy propionic, sorbic, alpha-chlorsorbic, cinnamic,beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic,glutaconic, aconitic, alpha-phenylacrylic, 2-benzyl acrylic,2-cyclohexylacrylic, angelic, umbellic, fumaric, maleic acids andanhydrides. Other different olefinic monomer copolymerizable with suchcarboxylic monomers include vinylacetate, vinyl chloride, dimethylmaleate and the like. Copolymers ordinarily contain sufficientcarboxylic salt groups for water-solubility.

Also useful herein are so-called carboxyvinyl polymers disclosed astoothpast components in U.S. Pat. No. 3,980,767 to Chown et al; U.S.Pat. No. 3,935,306 to Roberts et al; U.S. Pat. No. 3,919,409 to Perla etal; U.S. Pat. No. 3,911,904 to Harrison, and U.S. Pat. No. 3,711,604 toColodney et al. They are commercially available for example under thetrademarks Carbopol 934, 940 and 941 of B. F. Goodrich, these productsconsisting essentially of a colloidally water-soluble polymer ofpolyacrylic acid crosslinked with from about 0.75% to about 2.0% ofpolyallyl sucrose or polyallyl pentaerythritol as cross linking agent,the cross-linked structure and cross-linkages providing the desiredretention-enhancement by hydrophobicity and/or physical entrapment ofthe antibacterial agent or the like. Polycarbophil is somewhat similar,being polyacrylic acid cross-linked with less than 0.2% of divinylglycol, the lower proportion, molecular weight and/or hydrophobicity ofthis cross-linking agent tending to provide little or no retentionenhancement. 2,5-dimethyl-1,5-hexadiene exemplifies a more effectiveretention-enhancing cross-linking agent.

The synthetic anionic polymeric polycarboxylate component is most oftena hydrocarbon with optional halogen and O-containing substituents andlinkages as present in for example ester, ether and OH groups.

The AEA may also comprise natural anionic polymeric polycarboxylatescontaining retention-enhancing groups. Carboxymethyl cellulose and otherbinding agents gums and film-formers devoid of the above-defineddelivery-enhancing and/or retention-enhancing groups are ineffective asAEA's.

As illustrative of AEA's containing phosphinic acid and/or sulfonic aciddelivery enhancing groups, there may be mentioned polymers andcopolymers containing units or moieties derived from the polymerizationof vinyl or allyl phosphinic and/or sulfonic acids substituted as neededon the 1 or 2 (or 3) carbon atom by an organic retention-enhancinggroup, for example having the formula --(X)_(n) --R defined above.Mixtures of these monomers may be employed, and copolymers thereof withone or more inert polymerizable ethylenically unsaturated monomers suchas those described above with respect to the operative synthetic anionicpolymeric polycarboxylates. As will be noted, in these and otherpolymeric AEA's operative herein, usually only one acidicdelivery-enhancing group is bonded to any given carbon or other atom inthe polymer backbone or branch thereon. Polysiloxanes containing ormodified to contain pendant delivery-enhancing groups and retentionenhancing groups may also be employed as AEA's herein. Also effective asAEA's herein are ionomers containing or modified to contain delivery-andretention-enhancing groups. Ionomers are described on pages 546-573 ofthe Kirk Othmer Encyclopedia of Chemical Technology, third edition,Supplement Volume, John Wiley & Sons, Inc. copyright 1984, whichdescription is incorporated herein by reference. Also effective as AEA'sherein, provided they contain rare modified to containretention-enhancing groups, are polyesters, polyurethanes and syntheticand natural polyamides including proteins and proteinaceous materialssuch as collagen, poly (argenine) and other polymerized amino acids.

Without being bound to a theory, it is believed that the AEA, especiallypolymeric AEA, is generally and desirably an anionic film formingmaterial and is thought to attach to tooth surfaces and form acontinuous film over the surfaces, thereby preventing bacterialattachment to tooth surfaces. It is possible that the noncationicantibacterial agent forms a complex or other form of association withthe AEA, thus forming a film of a complex or the like of the two overtooth surfaces. The film forming property of the AEA and the enhanceddelivery property of the AEA and the enhanced delivery and retention ofthe antibacterial agent on tooth surfaces due to the AEA appears to maketooth surfaces unfavourable for bacterial accumulation particularlysince the direct bacteriostatic action of the antibacterial agentcontrols bacterial growth. Therefore, through the combination of threemodes of actions: 1) enhanced delivery, 2) long retention time on toothsurfaces, and 3) prevention of bacterial attachment to tooth surfacesthe oral composition is made efficacious for reducing plaque. Similarantiplaque effectiveness is attained on soft oral tissue at or near thegum line.

In the oral preparation dentifrice, an orally acceptable vehicleincluding a water-phase with humectant is present. The humecant ispreferably glycerine and/or sorbitol. Water is present typically inamount of at least about 3% by weight, generally about 3-35% andglycerine and/or sorbitol typically total about 6.5-75% by weight of theoral preparation dentifrice, more typically about 10-75%. Moreover,there is also present with the water-humectant vehicle a material whichis particularly effective to dissolve the antibacterial agent in saliva,typically in amount of about 0.5-50% by weight. Together with thissolubilizing material, the water-humectant phase typically amounts toabout 10-80% by weight of the oral preparation dentifrice. Referencehereto to sorbitol refers to the material typically as availablecommercially in 70% aqueous solutions. Significant amounts ofpolyethylene glycol, particularly of molecular weight of 600 or more,should be avoided since polyethylene glycol effectively inhibits theantibacterial activity of the noncationic antibacterial agent. Forinstance, polyethylene glycol (PEG) 600 when present with triclosan in aweight ratio of 25 triclosan:1 PEG 600 reduces the antibacterialactivity of triclosan by a factor of about 16 from that prevailing inthe absence of the polyethylene glycol.

Materials which substantially dissolve the antibacterial agent, topermit its delivery to the soft oral tissues at or near the gumline, areemployed in the present invention. Typical solubilizing materialsinclude the humectant polyols such as propylene glycol, dipropyleneglycol and hexylene glycol, cellosolves such as methyl cellosolve andethyl cellosolve, vegetable oils and waxes containing at least about 12carbon atoms in a straight chain such as olive oil, castor oil, andpetrolatum and esters such as amyl acetate, ethyl acetate, glyceryltristearate and benzyl benzoate. Propylene glycol is preferred. As usedherein, "propylene glycol" includes 1,2-propylene glycol and1,3-propylene glycol.

When the amount of substantially water-insoluble noncationicantibacterial agent is low, say up to about 0.3% by weight, as little asabout 0.5% by weight of the solubilizing agent can be sufficient tosolubilize the antibacterial agent. When higher amounts such as at leastabout 0.5% by weight, of antibacterial agent are present, it isdesirable that at least about 5% by weight, typically up to about 20% ormore by weight, of the solubilizing agent be present.

The pH of oral preparation dentifrice of the invention is generally inthe range of about 4.5 to about 9 or 10 and preferably about 6.5 toabout 7.5. It is noteworthy that the compositions of the invention maybe applied orally at a pH below 5 without substantially decalcifying orotherwise damaging dental enamel. The pH can be controlled with acid(e.g. citric acid or benzoic acid) or base (e.g. sodium hydroxide) orbuffered (as with sodium citrate, benzoate, carbonate, or bicarbonate,disodium hydrogen phosphate, sodium dihydrogen phosphate, etc.).

In this invention, the oral composition dentifrice may be substantiallygel in character, such as a gel dentifrice. Such gel oral preparationsgenerally contain silaneous dentally acceptable polishing material.Preferred polishing materials include crystalline silica having particlesized of up to about 5 microns, a mean particle size of up to about 1.1microns, and a surface area of up to about 50,000 cm.² /gm., silica gelor colloidal silica and complex amorphous alkali metal aluminosilicate.

When visually clear or opacified gels are employed, a polishing agent ofcolloidal silica, such as those sold under the trademark SYLOID asSyloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100or alkali metal aluminosilicate complexes (that is, silica containingalumina combined in its matrix) are particularly useful, since they areconsistant with gel-like texture and have refractive indices close tothe refractive indices of gelling agent-liquid (including water and/orhumectant) systems commonly used in dentifices.

The polishing material is generally present in the oral compositiondentifrices such as toothpaste cream paste or gel compositions in weightconcentrations of about 5% to about 30%.

In a gel toothpaste, the liquid vehicle may typically comprise about3-35% by weight of water, such as about 10-35%, and humectant in anamount ranging from about 6.5% to about 80%, such as about 10% to about80% by weight of the preparation. In clear gels where the refractiveindex is an important consideration, about 3-30% of water, 0 to about70% of glycerine and about 20-25% of sorbitol are preferably employed.The solubilizing material, typically present in amount of about 0.5-20%or more by weight, may be considered to be a part of the liquid vehiclein the oral preparation dentifrice as prepared. As indicated, thesolubilizing materials include polyol humectants such as propyleneglycol and dipropylene glycol.

The oral composition dentifrices typically contain a natural orsynthetic thickener or gelling agent in proportions of about 0.1 toabout 10%, preferably about 0.5 to about 5%. A suitable thickener issynthetic hectorite, a synthetic colloidal magnesium alkali metalsilicate complex clay available for example as Laponite (e.g. CP, SP2002,/D) marketed by Laporte Industries Limited. Laponite D analysisshows, approximately by weight, 58.00% SiO₂, 25.40% MgO, 3.05% Na₂ O,0.98% Li₂ O, and some water and trace metals. Its true specific gravityis 2.53 and it has an apparent bulk density (g./ml. at 8% moisture) of1.0.

Other suitable gelling agents or thickeners include Irish moss,i-carrageenan, gum tragacanth, starch, polyvinylpyrrolidone,hydroxyethypropyl cellulose, hydroxybutyl methyl cellulose,hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. availableas Natrosol), sodium carboxymethyl cellulose, and colloidal silica suchthose available as finely ground Syloid 244 and Sylodent 15.

Since there maybe a tendency for the dentifrice to separate into liquidand solid portions when about 5% by weight or more of the solubilizingmaterial such as propylene glycol is present and since excellentantiplaque effects can be obtained with small amounts of antibacterialagent which do not require so much solubilizing humectant to effectsolubilization, a preferred dentifrice contains about 0.25-0.35%, sayabout 0.3%, by weight of the antibacterial agent, about 1.5-2% by weightof the polycarboxylate and about 0.5%-1% by weight of the solubilizingmaterial.

Without being bound to a theory whereby the advantages of this inventionare achieved, it is believed that an aqueous, humectant vehicle isnormally solubilized in surfactant micelles in the mobile phase (thatis, not including gelling agent and polishing agent) of a dentifriceformula. The phase solution of dentifrice during use becomes dilutedwith saliva which causes triclosan to precipitate. However, thesolubilizing material of the present invention permits the antibacterialagent to remain in solution in the mobile phase in the presence ofsaliva and to effectively reach the soft oral tissues. Propylene glycolbeing a strong solubilizing humectant for triclosan, appears to preventits precipitating and permit its continued presence within the mobilephase. In this regard it is noted that propylene glycol is widely usedin drug delivery systems (for instance in European Patent Publication271,332) for its strong interaction with biological membranes. It may bethat in the oral cavity, triclosan is partitioned from the aqueousenvironment oral preparation into propylene glycol-surfactant emulsionand further that propylene glycol in the bulk mobile phase allowsgreater probability of triclosan emergence out of surfactant micelles,thereby rendering triclosan available for delivery into bacterial andsoft surfaces as well as onto tooth surfaces. Similar remarks apply toother water-insoluble noncationic antibacterial agents herein described.

The oral composition dentifrice may also contain a source of fluorideions, or fluoride-providing component, as anti-caries agent, in anamount sufficient to supply about 25 ppm to 5,000 ppm of fluoride ions.This compound may be slightly soluble in water or may be fullywater-soluble. They are characterized by their ability to releasefluoride ions in water and by substantial freedom from undesiredreaction with other compounds of the oral preparation. Among thesematerials are inorganic fluoride salts, such as soluble alkali metal,alkaline earth metal salts, or example, sodium fluoride, potassiumfluoride, ammonium fluoride, calcium fluoride, a copper fluoride such ascuprous fluoride, zinc fluoride, barium fluoride, sodium fluorosilicate,ammonium flourosilicate, sodium fluorozirconate, sodium fluorozirconate,sodium monofluorphosphate, aluminum mono-and di-fluorophosphate, andfluorinated sodium calcium pyrophosphate. Alkali metal and tinfluorides, such as sodium and stannous fluorides, sodiummonofluorophosphate (MFP) and mixtures thereof, are preferred.

The amount of fluorine-providing compound is dependent to some extentupon the type of compound, its solubility, and the type of oralpreparation, but it must be a non-toxic amount, generally about 0.0005to about 3.0% in the preparation. In a dentifrice preparation, e.g.dental gel, an amount of such compound which releases up to about 5,000ppm of F ion by weight of the preparation is considered satisfactory.Any suitable minimum amount of such compound may be used, but it ispreferably to employ sufficient compound to release about 300 to 2,000ppm, more preferably about 800 to about 1,500 ppm of fluoride ion.

Typically, in the cases of alkali metal fluorides, this component ispresent in an amount up to about 2% by weight, based on the weight ofthe preparation, and preferably in the range of about 0.05% to 1%. Inthe case of sodium monofluorophosphate, the compound may be present inan amount of about 0.1-3%, more typically about 0.76%.

It will be understood that, as is conventional, oral preparations are tobe sold or otherwise distributed in suitable labelled packages. Thus adentifrice gel will usually be in a collapsible tube, typicallyaluminum, lined lead or plastic, or other squeeze, pump or pressurizeddispenser for metering out the contents, having a label describing it,in substance, as a dentifrice gel or the like.

Organic surface-active agents are used in the compositions of thepresent invention to achieve increased prophylactic action, assist inachieving thorough and complete dispersion of the antiplaqueantibacterial agent throughout the oral cavity, and render the instantcompositions more cosmetically acceptable. The organic surface-activematerial is preferably anionic, nonionic or ampholytic in nature, and itis preferred to employ as the surface-active agent a detersive materialwhich imparts to the composition detersive and foaming properties.Suitable examples of anionic surfactants are water-soluble salts ofhigher fatty acid monoglyceride monosulfates, such as the sodium salt ofthe monosulfated monoglyceride of hydrogenated coconut oil fatty acids,higher alkyl sulfates such as sodium lauryl sulfate, alkyl arylsulfonates such as sodium dodecyl benzene sulfonate, higher alkylsulfoacetates, higher fatty acid esters of 1,2-dihydroxy propanesulfonate, and the substantially saturated higher aliphatic acyl amidesof lower aliphatic amino carboxylic acid compounds, such as those having12 to 16 carbons in the fatty acid, alkyl or acyl radicals, and thelike. Examples of the last mentioned amides are N-lauroyl sarcosine, andthe sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl,or N-palmitoyl sarcosine which should be substantially free from soap orsimilar higher fatty acid material. The use of these sarcosinatecompounds in the oral compositions of the present invention isparticularly advantageous since these materials exhibit a prolonged andmarked effect in the inhibition of acid formation in the oral cavity dueto carbohydrate breakdown in addition to exerting some reduction in thesolubility of tooth enamel in acid solutions. Examples of water-solublenonionic surfactants are condensation products of ethylene oxide withvarious reactive hydrogen-containing compounds reactive therewith havinglong hydrophobic chains (e.g. aliphatic chains of about 12 to 20 carbonatoms), which condensation products ("ethoxamers") contain hydrophilicpolyoxyethylene moieties, such as condensation products of poly(ethyleneoxide) with fatty acids, fatty alcohols, fatty amides, polyhydricalcohols (e.g. sorbitan monosterate) and polypropyleneoxide (e.g.Pluronic materials).

Surface active agent is typically present in amount of about 0.5-5% byweight, preferably about 1-2.5%. It is noteworthy, that surface activeagent may assist in the dissolving of the noncationic antibacterialagent and thereby diminish the amount of solubilizing humectant needed.

Various other materials may be incorporated in the oral preparations ofthis invention such as whitening agents, preservatives, silicones,chlorophyll compounds and/or ammoniated material such as urea,diammonium phosphate, and mixtures thereof. These adjuvants, wherepresent, are incorporated in the preparations in amounts which do notsubstantially adversely affect the properties and characteristicsdesired. Significant amounts of zinc, magnesium and other metal saltsand materials which are generally soluble and which would complex withactive components of the instant invention are to be avoided.

Any suitable flavoring or sweetening material may also be employed.Examples of suitable flavoring constituents are flavoring oils, e.g. oilof spearmint, pepperment, wintergreen, sassafras, clove, sage,eucalyptus, marjoram, cinnamon, lemon, and orange, and methylsalicylate. Suitable sweetening agents include sucrose, lactose,maltose, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenylalanine, methyl ester), saccharine and the like. Suitably, flavor andsweetening agents may each or together comprise from about 0.1% to 5%more of the preparation. Moreover, flavor oil is believed to aid thedissolving of the anti-bacterial agent.

In the preferred practice of this invention an oral compositiondentifrice containing the composition of the present invention ispreferably applied regularly to dental enamel and soft oral tissues,particularly at or near the gum line, such as every day or every secondor third day or preferably from 1 to 3 times daily, at a pH of about 4.5to about 9, generally about 5.5 to about 8, preferably about 6.5 to 7.5,for at least 2 weeks up to 8 weeks or more up to lifetime.

The composition of this invention can be incorporated in lozenges, or inchewing gum or other products, e.g. by stirring into a warm gum base orcoating the outer surface of a gum base, illustrative of which may bementioned jelutong, rubber latex, vinylite resins, etc., desirably withconventional plastizers or softeners, sugar or other sweeteners orcarbohydrates such as glucose, sorbitol and the like.

EXAMPLE A Poly (beta-styrenephosphonic acid)

A mixture of 18.1 g. (0.1M) of beta-styrenephosphonic acid and 0.82 g.(0.005M) of azobisisobutyronitrile (AIBN) in 300 ml. of anhydrousacetonitrile is stirred under reflux under dry nitrogen for 96 hrs. Themixture is cooled and the crude product precipitate is isolated byfiltration, washed with acetonitrile, and air dried. The crude productis dissolved in aqueous sodium hydroxide (to pH 11) and dialyzed againstwater at 3000 Dalton cutoff. The retentate solution is reduced to 100ml., in vacuo, and freeze-dried to yield the purified product polymer asa white powdery solid in 0.91 g. yield. Infrared spectrum: 1610, 1550,745 cm⁻¹ (aryl,5 adjacent H); 1240, 1020, 950 cm⁻¹ (phosphonate). Protonnmr (D>O): tr, 6.4 ppm. (H on carbon bearing phosphonate); m, 7.3 ppm.(aryl and benzylic protons); area ratio 1 to 6. Phosphorus nmr (D>O):m,6.2 ppm. (alkyl phosphonate).

EXAMPLE B Copoly (beta-styrenephosphonic acid/vinylphosphonic acid)

A mixture of 10.68 g. (0.058M) of beta-styrenephosphonic acid, 6.0 ml.(8.4 g., 0.058M) of vinylphosphonyl dichloride, and 0.5 g. of AIBN isheated, with stirring, under an anhydrous nitrogen atmosphereintermittently for a few hours, then overnight at 80°-90° C. Thematerial is transferred to a beaker with 60-70 ml. of water. Acrystalline precipitate forms as the warm solution cools. The mixture isfiltered, the aqueous filtrate is diluted to 125 ml. with water, and theresulting solution is dialyzed vs. water at 3500 Dalton cutoff. Theretentate solution is evaporated in vacuo to give 0.600 g. purified acidform of the copolymer. Proton nmr (D>O) shows two broad regions at1.0-2.8 (alkyl, 11H) and 6.9-7.5 ppm. (aryl, 5H). These data indicate aratio of beta-styrenephosphonic acid to vinylphosphonic acid of 1:3 inthe copolymer. Phosphorus nmr (D>O) shows two main phosphorus signalscentered at about 23.4 and 29.2 ppm. respectively.

EXAMPLE C Poly (alpha-styrenephosphonic acid)

A mixture of 2.21 g. (0.01M) of alpha-styrenephosphonyl dichloride and0.01 g. of AIBN is stirred under a nitrogen atmosphere at 115° C. At 12hour intervals, successive 0.01 g. AIBN portions are added to themixture. After 96 hours, the mixture is allowed to cool and dissolved inwater. The pH is adjusted to 8-10 with aq. sodium hydroxide in a totalvolume of 125 ml. The solution is filtered and the filtrate is dialyzedagainst water in a 3500 Dalton cutoff cellulose bag. The retentate isreduced to about 50 ml. in vacuo, then freeze dried. The polymer isobtained as a tan powdery solid in 0.08 g. yield. Proton nmr (D>O):7.2-7.4 ppm. (m, phenyl). Phosphorus nmr (D>O): 23-25 ppm. (m).

The following examples are further illustrative of the nature of thepresent invention, but it is understood that the invention is notlimited thereto. All amounts and proportions referred to herein and inthe appended claims are by weight, unless otherwise indicated.

EXAMPLE 1

The effect of synthetic anionic linear polycarboxylate on the uptake,retention to and release from tooth surfaces of water-insolublenoncationic antibacterial agent is assessed in vitro on a saliva coatedhydroxyapatite disk and on exfoliated buccal epithelial cells. The invitro assessments are correlatable to in vivo delivery, and retention onoral surfaces.

For the test of delivery of antibacterial agent to a saliva coatedhydroxyapatite disk, hydroxyapatite (HA) obtained from the MonsantoColo. is washed extensively with distilled water, collected by vacuumfiltration, and permitted to dry overnight at 37° C. The dried HA isground into a powder with a mortar and pestle. 150.00 mgs of HA areplaced into the chamber of a KBr pellet die (Barnes Analytical,Stanford, Conn.) and compressed for 6 minutes at 10,000 pound in aCarver Laboratory press. The resulting 13 mm disks are sintered for 4hours at 800° C. in a Thermolyne furnace. Parafilm stimulated wholesaliva is collected into an ice-chilled glass beaker. The saliva isclarified by centrifugation at 15,000 Xg (times gravity) for 15 minutesat 4° C. Sterilization of the clarified-saliva is done at 4° C. withstirring by irradiation of the sample with UV light for 1.0 hour.

Each sintered disk is hydrated with sterile water in a polyethylene testtube. The water is then removed and replaced with 2.00 ml of saliva. Asalivary pellicle is formed by incubating the disk overnight at 37° C.with continuous shaking in a water bath. After this treatment, thesaliva is removed and the disks are treated with 1.00 ml of a solutioncontaining antibacterial agent (Triclosan) dentifrice liquid phasesolution and incubated at 37° C. with continuous shaking in the waterbath. After 30 minutes, the disk is transferred into a new tube and 5.00ml of water are added followed by shaking the disk gently with a Vortex.The disk is then transferred into a new tube and the washing procedurerepeated twice. Finally, the disk is transferred carefully into a newtube to avoid co-transfer of any liquid along with the disk. Then 1.00ml of methanol is added to the disk and shaken vigorously with a Vortex.The sample is left at room temperature for 30 minutes to extractadsorbed Triclosan into the methanol. The methanol is then aspirated andclarified by centrifugation in a Beckman Microfuge 11 at 10,000 rpm to 5minutes. After this treatment, the methanol is transferred into HPLC(high performance liquid chromatography) vials for determination ofantibacterial agent. Triplicate samples are used in all experiments.

For the test of retention of antibacterial agent to a saliva coated HAdisk, a saliva coated HA disk is treated with dentifrice slurries asdescribed above. After incubation for 30 minutes at 37° C., the HA diskis removed from the dentifrice slurry, washed twice with water, and thenreincubated with parafilm stimulated human whole saliva which had beenclarified by centrifugation. After incubation at 37° C. with constantshaking for various periods, the HA disk is removed from the saliva, andthe amount of antibacterial agent (Triclosan) retained onto the disk andreleased into saliva is determined by analytical method using HPLC.

For the assay of delivery of antibacterial agent to buccal epithelialcells, the delivery is measured in order to determine the effect ofPVM/MA on the delivery of antibacterial agent (Triclosan) to soft oraltissue from a dentifrice product. Buccal epithelial cells are collectedwith a wooden applicator stick by gently rubbing the oral mucosa. Thecells are suspended in Resting Saliva Salts (RSS) Buffer (50 mM NaCl,1.1 mM CaCl₂, and 0.6 mM KH₂ PO₄ pH 7.0) to 5-6×10⁵ cells/ml using ahemocytometer to enumerate the cells and kept in ice until use. 0.5 mlof cell suspension, preincubated to 37° C. in a waterbath, is added with0.5 ml of the test antibacterial agent solution and incubated at 37° C.The antibacterial agent solution in the incubation mixture is diluted atleast 10 times in order to lower the surfactant concentration andprevent destruction of cell membranes by the surfactant. After 30minutes of incubation, the cells are harvested by centrifugation inBeckman Microfuge 11 at 5,000 rpm for 5 minutes. The cells, collected asthe pellet, are washed 3 times with RSS buffer and treated with 1.5 mlof methanol. The sample is mixed vigorously by Vortex and thencentifuged as described above. The supernatant is analyzed forantibacterial agent by the HPLC method.

Dentifrices are prepared having the following formulas:

    ______________________________________                                                        Parts                                                                         A        B                                                    ______________________________________                                        Propylene Glycol (1,2)                                                                          10.00      10.00                                            Iota Carrageenan  0.75       0.75                                             Gantrez S-97      --         2.00                                             Titanium Dioxide  0.50       0.50                                             Sorbitol (70%)    30.00      30.00                                            Sodium Fluoride    0.332      0.332                                           Sodium Saccharin  0.40       0.40                                             Silica Thickener (Sylodent 15)                                                                  3.00       3.00                                             Silica Polishing Agent                                                                          20.00      20.00                                            (Zeodent 113)                                                                 Triclosan         0.20       0.20                                             Sodium Lauryl Sulfate                                                                           2.00       2.00                                             Flavor Oil        0.95       0.95                                             Ethyl Alcohol     1.00       1.00                                             Sodium Hydroxide (50%)                                                                          0.80       0.80                                             Water             Q.S. to 100.0                                                                            Q.S. to 100.0                                    ______________________________________                                    

The uptake of triclosan on the saliva coated hydroxyapatite disk and onbuccal epithelial cells with and without the polymeric polycarboxylate,Gantrez S-97, is set forth in Table 1 below:

                  TABLE 1                                                         ______________________________________                                                  Uptake of Triclosan                                                                           In Micrograms                                                 in micrograms   × 10.sup.5 Buccal                             Dentifrice                                                                              On Saliva Coated Disk                                                                         Epithelial Cells                                    ______________________________________                                        A         25.0            38.0                                                B         54.0            96.0                                                ______________________________________                                    

These results reveal that the Gantrez material (present in Dentifrice B)greatly enhances the delivery and uptake of triclosan to saliva coatedhydroxyapatite disk and to the exfoliated buccal epithelial cells.

Similar results are obtained when the dentifrices contain 0.30 parts oftricolosan.

EXAMPLE 2

In tests with saliva coated hydroxapatite disks and exfoliated buccalepithelical cells different from those set forth in Example 1 above,said dentifrice B containing 2.00% Gantrez S-97 and 0.20% of triclosan,10.00% of propylene glycol and 2.00% of sodium lauryl sulfate and anequivalently formulated Dentifrice (B'), except for the presence of0.30% of triclosan were compared with a commercially availableDentifrice (C) containing hydrated alumina polishing agent and (a) 0.2%of triclosan, (b) no Gantrez material, (c) no propylene glycol, (d) 0.5%zinc citrate, (e) 2.5% of surface active agents (f) sodiummonofluorophosphate and hydrated alumina polishing agent; and thedentifrice formulation below (C') which is similar to commercialDentifrice C except for the presence of 0.30% of triclosan:

    ______________________________________                                        DENTIFRICE C'                                                                                     %                                                         ______________________________________                                        Sorbitol (70%)        27.00                                                   Sodium Carboxymethyl Cellulose                                                                      0.80                                                    Sodium Monofluorophosphate                                                                          0.85                                                    Zinc Citrate          0.50                                                    Sodium Saccharin      0.18                                                    Water                 16.47                                                   Hydrated Alumina Polishing Agent                                                                    50.00                                                   Ethanol               0.20                                                    Sodium Lauryl Sulfate 1.875                                                   Sodium Dodecyl Benzene Sulfonate                                                                    0.625                                                   Triclosan             0.30                                                    Flavor                1.20                                                    ______________________________________                                    

Since Dentifrices C and C' contain a total of 2.50% of surface activeagent, more surface active agent is available to dissolve triclosan thanin Dentifrices B and B' which contain 2.00%. However, propylene glycolpresent in siliceous polishing agent Dentifrices B and B' (but not inhydrated alumina polishing agent Dentifrices C and C') insures optimumdissolution of triclosan.

The advantage of Dentifrices B and B' (containing propylene glycol) andGantrez) over Dentifrices C and C' in triclosan uptake on saliva coatedhydroxyapatite disks and on exfoliated buccal epithelial cells is shownin the Table 2 below:

                  TABLE 2                                                         ______________________________________                                                Delivery of Triclosan                                                         To Saliva Coated                                                                           To Buccal Epithelial                                             Hydroxyapatite Disk                                                                        Cells in micrograms                                              (in micrograms)                                                                            × 10.sup.6 Epithelial Cells)                       ______________________________________                                        Dentifrice                                                                            B     41.1           101.6                                                    B'    77.4           142.0                                                    C     20.4           61.0                                                     C'    42.6           100.0                                            ______________________________________                                    

Additional experiments with Dentifrice B' (0.3% Triclosan; Gantrez;Propylene Glycol) in a 50% slurry of the dentifrice to determine theretention of triclosan on the saliva coated hydroxyapatite disk over aperiod of time reveals retention of excellent levels of triclosan asshown in Table 3 below:

                  TABLE 3                                                         ______________________________________                                        Retention of Triclosan Adsorption                                             from Dentifrice Slurry                                                        Time         Retention of Triclosan                                           (in Minutes) (Micrograms/Disk)                                                ______________________________________                                         0           70                                                                30          60                                                                60          70                                                               120          65                                                               180          57                                                               240          59                                                               ______________________________________                                    

These results indicate that dentifrices containing triclosan, Gantrezmaterial and propylene glycol can provide enhanced delivery of triclosanto, and retention on, tooth surfaces and soft surfaces in the oralcavity, thereby providing improved antiplaque and antibacterial effects.

EXAMPLE 3

For purpose of comparison formulas a and b below are prepared

    ______________________________________                                        Dentifrice                                                                                       %                                                                             a     b                                                    ______________________________________                                        Glycerin             10.00   --                                               Propylene Glycol     --      10.00                                            Iota Carrageenan     0.60    0.60                                             Sorbitol (70%)       25.00   25.00                                            Sodium Saccharin     0.40    0.40                                             Sodium Fluoride       0.243   0.243                                           Titanium Dioxide     0.50    0.50                                             Gantrez S-97         2.00    2.00                                             Water                29.157  29.157                                           NaOH (50%)           2.00    2.00                                             Zeodent 113          20.00   20.00                                            (Silica Polishing Agent)                                                      Sylodent 15 (Silica Thickener)                                                                     5.50    5.50                                             Flavor               1.10    1.10                                             Triclosan            0.50    0.50                                             Sodium Lauryl Sulfate                                                                              2.00    2.00                                             Ethanol              1.00    1.00                                             ______________________________________                                    

Formula a is a dentifrice containing a Gantrez polycarboxylate, withtriclosan as an antibacterial antiplaque agent and no solublizing agent.In Formula b, propylene glycol solubilizing agent is present.

Formula a is poor in delivery of triclosan on buccal epithelial cellswhile Formula b is markedly effective.

The foregoing results reveal excellent delivery of Triclosan dentifrice.

EXAMPLE 4

An "in-house" study was conducted on a group of volunteers to assess theeffects of particular dentifrices in influencing plaque regrowth inaccordance with the method described by Addy, Willis and Moran, J. Clin.Perio., 1983, Vol. 10, Pages 89-99. The dentifrices tested included aplacebo control containing no triclosan (i) and a dentifrice inaccordance with this invention containing 0.3% of triclosan, 10%propylene glycol (instead of 3% polyethylene glycol 600) and 2% ofGantrez S-97 and humectant of propylene glycol and sorbitol (ii). Theformulas of the dentifrices are as follows:

    ______________________________________                                                           Parts                                                                         (i)    (ii)                                                                   Placebo                                                                              Invention                                           ______________________________________                                        Polyethylene Glycol 600                                                                            3.00     --                                              Glycerine            25.00    --                                              Propylene Glycol     --       10.00                                           Sorbitol (70%)       41.617   25.00                                           Sodium Carboxymethyl Cellulose                                                                     0.35     --                                              Iota Carrageenan     --       0.60                                            Sodium Benzoate      0.50     --                                              Sodium Saccharin     0.20     0.40                                            Sodium Fluoride       0.243    0.243                                          Silica Polishing Agent                                                                             18.00    20.00                                           (Zeodent 113)                                                                 Silica thickener     5.50     5.50                                            (Sylox 15)                                                                    Water                3.00     28.757                                          Gantrez S-97         --       2.00                                            Triclosan            --       0.30                                            Titanium Dioxide     0.50     0.50                                            Sodium Lauryl Sulfate                                                                              1.20     2.50                                            Flavor               0.89     1.10                                            Ethyl Alcohol                 1.00                                            Sodium Hydroxide (50%)        2.00                                            ______________________________________                                    

With regard to plaque reduction, on the teeth of the volunteers,compared to placebo (i), invention (ii) provided a significant decreaseof 20%.

Since lesser amounts of propylene glycol can dissolve the 0.3% oftriclosan present in Toothpaste (ii), similar results are expected whenthe amount of propylene glycol is reduced to 0.5 parts and the amount ofsorbitol is increased to 39.5 parts. Likewise, the other solubilizingmaterials dipropylene glycol, hexylene glycol, methyl cellosolve, ethylcellosolve, olive oil, castor oil, petrolatum, amyl acetate, ethylacetate, glyceryl tristearate and benzyl benzoate., in place ofpropylene glycol, can effectively deliver triclosan to soft oraltissues.

EXAMPLE 5

The following dentifrices of the invention are prepared:

    ______________________________________                                                            Parts                                                                         A     B                                                   ______________________________________                                        Glycerine             --      20.00                                           Propylene Glycol      10.00   0.50                                            Sorbitol (70%)        25.00   19.50                                           Sodium Carboxymethyl Cellulose                                                                      --      1.10                                            Iota Carrageenan       0.600  --                                              Sodium Saccharin      0.40    0.30                                            Sodium Fluoride        0.243   0.243                                          Silica Polishing Agent                                                                              20.00   20.00                                           (Zeodent 113)                                                                 Silica thickener (Sylox 15)                                                                         5.50    3.00                                            Water                 28.757  15.307                                          Gantrez S-97          2.00    2.00                                            Triclosan             0.50    0.30                                            Titanium Dioxide      0.50    0.50                                            Sodium Lauryl Sulfate 2.50    2.00                                            Flavor                1.10    0.95                                            Ethanol               1.00    --                                              Sodium Hydroxide (50%)                                                                              2.00    1.60                                            ______________________________________                                    

In the foregoing examples, improved results may also be obtained byreplacing triclosan with other antibacterial agents herein describedsuch as phenol, thymol, eugenol and 2,2'-methylene bis(4-chloro-6-bromophenol) and/or by replacing Gantrez with other AEA'ssuch as a 1:1 copolymer of maleic anhyride and ethyl acrylate,sulfoacrylic oligomers, Carbopols (e.g. 934), polymers of monomericalpha- or beta-styrene phosphonic acid and copolymers of these styrenephosphonic acid monomers with each other or with other ethylenicallyunsaturated polymerizable monomers such as vinyl phosphonic acid.

EXAMPLE 6

The following liquid phase dentifrice solutions are tested for uptakeand retention of triclosan on saliva coated HA disks following the testprocedures described in Example 1 with the indicated results:

    ______________________________________                                                       Parts                                                          Ingredients      A       B       C     D                                      ______________________________________                                        Sorbitol (70% solution)                                                                        30.0    30.0    30.0  30.0                                   Glycerol         9.5     9.5     9.5   9.5                                    Propylene Glycol 0.5     0.5     0.5   0.5                                    SLS              20.0    20.0    20.0  20.0                                   NaF              0.243   0.243   0.243 0.243                                  Flavor Oil       0.95    0.95    0.95  0.95                                   Triclosan        0.3     0.3     0.3   0.3                                    Water            56.507  54.507  54.507                                                                              54.507                                 Poly (beta-styrenephosphonic                                                                           2.0                                                  acid)                                                                         Poly (alpha-styrenephosphonic    2.0                                          acid)                                                                         Polyvinyl Alcohol                      2.0                                    Adjusted to pH 6.5 with NaOH                                                                   31.0    174.0   86.0  36.0                                   Triclosan Uptake in                                                           Micrograms on Saliva Coated                                                   Disks                                                                         Retention of Triclosan on                                                     Saliva Coated HA Disks                                                        After:                                                                        Initial                  183.0                                                30 minutes               136.0                                                1 hour                   105.0                                                3 hours                  83.0                                                 ______________________________________                                    

The above results show that solution (D) containing polyvinyl alcohol,not an AEA hereunder, produced a triclosan uptake of only 36.0, quitesimilar to the 31.0 uptake of the control solution (A) without additive.In contrast, solution (C) with poly (alpha-styrenephosphonic acid)produces an uptake of 86.0, more than double that of solutions (A) and(D), and solution (B) with poly (beta-styrenephosphonic acid) producesan uptake about 5 times that of solutions (A) and (D), tending toindicate further that vicinal substitution of the delivery-enhancinggroup yields superior results. The above results also show thesurprisingly good retention of triclosan on the HA disks over timeobtained with solution (B) containing poly (betastyrenephosphonic acid(M.W's about 3,000 to 10,000).

This invention has been described with respect to certain preferredembodiments and it will be understood that modifications and variationsthereof obvious to those skilled in the art are to be included withinthe spirit and purview of this application and the scope of the appendedclaims.

We claim:
 1. An oral composition dentifrice for attaching, adhering orbonding a plaque-inhibiting antibacterial agent to oral tooth and gumsurfaces comprising in an orally acceptable vehicle about 5-30% byweight of a siliceous polishing agent, an effective antiplaque amount inthe range of about 0.01-5% by weight of a substantially water insolublenon-cationic antibacterial agent, about 0.05-5% by weight of anantibacterial-enhancing agent which contains at least onedelivery-enhancing functional group and at least one organicretention-enhancing, which delivery-enhancing group enhances delivery ofsaid antibacterial agent to oral tooth and gum surfaces and saidretention-enhancing group enhances attachment, adherence or bonding ofsaid antibacterial agent on oral tooth and gum surfaces, and about0.5-50% by weight of a solubilizing material for said antibacterialagent in amount sufficient to dissolve said antibacterial agent insaliva and permit delivery of said antibacterial agent to soft oraltissues at or near the gum line.
 2. The oral composition claimed inclaim 1, wherein said antibacterial agent is selected from the groupconsisting of halogenated diphenyl ethers, halogenated salicylanilides,benzoic esters, halogenated carbanilides and phenolic compounds.
 3. Theoral composition claimed in claim 2, wherein said antibacterial agent isa halogenated diphenyl ether.
 4. The oral composition claimed in claim3, wherein said halogenated diphenyl ether is2,4,4'-trichloro-2'-hydroxydiphenyl ether.
 5. The oral compositionclaimed in claim 2, wherein said antibacterial agent is a phenoliccompound.
 6. The oral composition claimed in claim 5, wherein saidphenolic compound is selected from the group consisting of phenol,thymol, eugenol, and 2,2'-methylene bis(4-chloro-6-bromophenol).
 7. Theoral composition claimed in claim 1, wherein said antibacterial agent ispresent in amount of about 0.25-5% by weight.
 8. The oral compositiondentifrice claimed in claim 1, wherein said solubilizing material isselected from the group consisting of propylene glycol, dipropyleneglycol, hexylene glycol, methyl cellosolve, ethyl cellosolve, vegetableoil and wax containing at least 12 carbon atoms, amyl acetate, ethylacetate, glycerol tristearate and benzyl benzoate.
 9. The oralcomposition dentifrice claimed in claim 8, wherein aid solubilizingmaterial is propylene glycol.
 10. The oral composition dentifriceclaimed in claim 1, wherein said antibacterial-enhancing agent is watersoluble or swellable.
 11. The oral composition claimed in claim 10,wherein said antibacterial-enhancing agent has an average molecularweight of about 100 to about 1,000,000.
 12. The oral composition claimedin claim 11, wherein said delivery-enhancing group is acidic.
 13. Theoral composition claimed in claim 12, wherein said delivery-enhancinggroup is selected from the group consisting of carboxylic, phosphonic,phosphinic and sulfonic acids, and their salts, and mixtures thereof,and wherein said organic retention-enhancing group comprises the formula--(X)_(n) --R wherein X is O, N, S, SO, SO₂, P, PO or Si, R ishydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic,or their inert-substituted derivatives, and n is zero or one or more,and wherein said antibacterial-enhancing agent is a monomer or polymerselected from the group consisting of oligomers, homopolymers,copolymers of two or more monomers, ionomers, block copolymers, graftcopolymers, and crosslinked polymers and monomers.
 14. The oralcomposition claimed in claim 13, wherein said antibacterial-enhancingagent is an anionic polymer containing a plurality of saiddelivery-enhancing and retention-enhancing groups.
 15. The oralcomposition claimed in claim 14, wherein said anionic polymer comprisesa chain containing repeating units each containing at least one carbonatom.
 16. The oral composition claimed in claim 15, wherein each unitcontains at least one delivery-enhancing group and at least one organicretention-enhancing group bonded to the same or vicinal or other atomsin the chain.
 17. An oral composition dentifrice comprising in an orallyacceptable vehicle, about 5-30% of a siliceous polishing agent, about0.01-5% of triclosan, about 0.05-5% of poly(beta-styrenephosphonicacid), poly(alpha-styrenephosphonic acid), or a copolymer of etherstyrenephosphonic acid and monomer with the other or with another inertpolymerizable ethylenically unsaturated monomer and propylene glycol inamount sufficient to dissolve the triclosan in saliva.